Low Vitamin D and High Fibroblast Growth Factor 23 Serum Levels Associate with Infectious and Cardiac Deaths in the HEMO Study

Abstract

In contrast, the highest FGF23 quartile was associated with a higher risk of infectious events (HR, 1.57 versus the lowest quartile; 95% CI, 1.13-2.18), cardiac events (HR, 1.49; 95% CI, 1.06-2.08), and allcause mortality (HR, 1.50; 95% CI, 1.07-2.12) in fixed-covariate Cox models. The addition of inflammation markers into the statistical models did not attenuate these associations. Thus, disordered mineral metabolism may affect outcomes in chronic hemodialysis patients. Cardiac events are the major cause of death in hemodialysis patients, accounting for approximately 40-50% of deaths. 1,2 Similarly, infections remain a very common cause of morbidity and mortality. [3][4][5] Several nontraditional risk factors may contribute to these two important clinical outcomes in this high-risk population, such as CKDassociated mineral and bone disorder 6 which includes a wide range of abnormalities in vitamin D metabolism 7-9 and phosphate homeostasis. 10,11 Lower serum levels of both 25-hydrovitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) have been associated with increased mortality within 90 days of initiating hemodialysis. 8 However, no studies have evaluated annual repeated measures of vitamin D analytes in

FGF23 signaling impairs neutrophil recruitment and host defense during CKD

“…It has been described that FGF23 may inhibit the extrarenal expression of vitamin D-activating enzyme 1α-hydroxylase in monocytes, thus regulating 1,25-dihydroxyvitamin D synthesis (32,33). Moreover, a recently published study among chronic hemodialysis patients demonstrated that increased FGF23 levels were independently associated with a higher infection rate and higher all-cause mortality (18). However, this study included dialysis patients, and the mechanisms might differ from the data in our study.…”

“…FGF23 levels are often 2-to 5-fold above the normal range during early and intermediate stages of CKD, but they can reach levels 1,000-fold above normal in advanced renal failure (13,14). While compensatory increases in FGF23 levels help patients with CKD to maintain normal serum phosphate levels despite even severely reduced renal function, recent prospective studies of CKD and non-CKD patients demonstrated that elevated FGF23 levels during CKD are independently associated with infectious events and all-cause mortality, and they have a dose-dependent association between elevated FGF23 levels and greater risks of major cardiovascular events and mortality (13,(15)(16)(17)(18). Although leukocytes express different high-affinity tyrosine kinase receptors (FGFR1, -2, and -4) -with FGFR2 being the only cell surface-bound FGFR -the effects of FGF23 on integrin activation and neutrophil activation and recruitment have not been investigated yet (19).…”

Associations of Fibroblast Growth Factor 23 with Markers of Inflammation and Leukocyte Transmigration in Chronic Kidney Disease

“…These immunological distu rbances are in turn associated with cardiovascular di sease such as atherosclerosis [34] and accelerated loss of kidney function [35] as well as increased suscepti bility to infection. Similarly, elevated FGF23 levels in plasma are associated with these outcomes and thus a potential culprit for inflicting immunological distu rbances in CKD [36].…”

Does calcium channel blockade have a role in prevention of expression of sepsis in renal transplant recipients?

“…33 Simultaneously, the Hauser research group demonstrated that the predisposition of trauma patients to pneumonia 34 with the accompanying inflammatory response syndrome (adult respiratory distress syndrome) could be reduced in the animal model with normalization of chemokine expression by use of calcium channel blockers. 35 An increased prevalence of severe infections, most of which occur in the upper respiratory tract is noted in patients with low vitamin D levels with 36 or without 37,38 advanced kidney disease. Patients treated for sepsis in the intensive care setting may suffer the consequences of excessive inflammatory reaction as adult acute respiratory distress syndrome.…”